DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1142 types of thyroid dysfunction, women are affected more
than men, with a ratio ranging from 5:1-7:1. Graves’ disease
is more common between the ages of 20 and 50,
but it may occur at any age. Major histocompatibility
alleles (HLA) B 8
and DR 3
are associated with Graves’
disease in whites. Graves’ disease is commonly associated
with other autoimmune diseases.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
The characteristic exophthalmos associated with Graves’ disease
is an infiltrative ophthalmopathy and is considered an autoimmunemediated
inflammation of the periorbital connective tissue and
extraocular muscles. This disorder is clinically evident with various
degrees of severity in ~50% of patients with Graves’ disease, but it
is present on radiological studies, such as ultrasound or CT scan, in
almost all patients. The pathogenesis of Graves’ ophthalmopathy,
including the role of the TSH receptor present in retro-orbital tissues,
and the management of this disorder, remain controversial
(Khoo and Bahn, 2007).
Toxic uninodular/multinodular goiter accounts for 10-40%
of cases of hyperthyroidism and is more common in older patients.
Infiltrative ophthalmopathy is absent.
A low RAIU is seen in the destructive thyroiditides and in
thyrotoxicosis resulting from exogenous thyroid hormone ingestion.
Low RAIU thyrotoxicosis caused by subacute (painful) and silent
(painless or lymphocytic) thyroiditis represents ~5-20% of all cases.
Silent thyroiditis occurs in 7-10% of postpartum women in the U.S.
(Abalovich et al., 2007). Other causes of thyrotoxicosis are much
less common.
Most of the signs and symptoms of thyrotoxicosis stem from
the excessive production of heat, increased motor activity, and
increased sensitivity to catecholamines produced by the sympathetic
nervous system. The skin is flushed, warm, and moist; the muscles
are weak and tremulous; the heart rate is rapid, the heartbeat is forceful,
and the arterial pulses are prominent and bounding. Increased
expenditure of energy gives rise to increased appetite and, if intake
is insufficient, to loss of weight. There also may be insomnia, difficulty
in remaining still, anxiety and apprehension, intolerance to
heat, and increased frequency of bowel movements. Angina, arrhythmias,
and heart failure may be present in older patients. Older
patients may experience less manifestations of sympathetic nervous
system stimulation, so called apathetic hyperthyroidism. Some individuals
may show extensive muscular wasting as a result of thyroid
myopathy. Patients with long-standing undiagnosed or undertreated
thyrotoxicosis may develop osteoporosis due to increased bone
turnover (Murphy and Williams, 2004).
The most severe form of hyperthyroidism is thyroid
storm, which is discussed later in the discussion of
therapeutic uses of anti-thyroid drugs.
Thyroid Function Tests. The development of radioimmunoassays
and, more recently, chemiluminescent and enzyme-linked
immunoassays for T 4
, T 3
, and TSH have greatly improved the laboratory
diagnosis of thyroid disorders (Demers and Spencer, 2003).
However, measurement of the total hormone concentration in
plasma may not give an accurate picture of the activity of the thyroid
gland. The total hormone concentration changes with alterations
in either the amount of TBG in plasma or the binding affinity of
TBG for hormones. Although equilibrium dialysis of undiluted
serum and radioimmunoassay for free thyroxine (FT 4
) in the
dialysate represent the gold standard for determining FT 4
concentrations,
this assay is typically not available in routine clinical laboratories.
The FT 4
index is an estimation of the FT 4
concentration
and is calculated by multiplying the total thyroxine concentration
by the thyroid hormone binding ratio, which estimates the degree
of saturation of TBG. The most common assays used for estimating
the free T 4
and free T 3
concentrations employ labeled analogs
of these iodothyronines in chemiluminescence and enzyme-linked
immunoassays. These assays correlate well with free T 4
concentrations
measured by the more cumbersome equilibrium dialysis
method and are easily adaptable to routine clinical laboratory use.
However, the analog assays are affected by extremes of serum
binding proteins as well as a wide variety of non-thyroidal disease
states, including acute illness, and by certain drugs to a greater
degree than are the free T 4
index and free T 4
determined by equilibrium
dialysis.
In individuals with normal pituitary function, serum measurement
of TSH is the thyroid function test of choice because pituitary
secretion of TSH is sensitively regulated in response to
circulating concentrations of thyroid hormones.
A major use of the TSH assay is to differentiate between normal
and thyrotoxic patients, who should exhibit suppressed TSH values.
Indeed, the sensitive TSH assay has replaced evaluation of the
response of TSH to injection of synthetic TRH (TRH stimulation
test) in the thyrotoxic patient. Although the serum TSH assay is
extremely useful in determining the euthyroid state and titrating the
replacement dose of thyroid hormone in patients with primary
hypothyroidism, abnormal serum TSH concentrations may not
always indicate thyroid dysfunction. In such patients, assessment of
the circulating thyroid hormone levels will further determine whether
or not thyroid dysfunction is truly present. Synthetic preparations of
TRH (protirelin) are no longer available in the U.S. for the evaluation
of pituitary or hypothalamic failure as a cause of secondary
hypothyroidism.
Recombinant human TSH (thyrotropin alfa, THYROGEN) is
available as an injectable preparation to test the ability of thyroid tissue,
both normal and malignant, to take up radioactive iodine and
release thyroglobulin (Duntas and Cooper, 2008; Haugen et al.,
1999; Pacini and Castangna, 2008).
Therapeutic Uses of Thyroid Hormone
The major indications for the therapeutic use of thyroid
hormone are for hormone replacement therapy in
patients with hypothyroidism and for TSH suppression
therapy in patients with thyroid cancer. Other less common
uses also are discussed.
Thyroid Hormone Preparations. Synthetic preparations of
the sodium salts of the natural isomers of the thyroid
hormones are available and widely used for thyroid hormone
therapy.
Levothyroxine. Levothyroxine sodium (L-T 4
, LEVOTHROID,
LEVOXYL, SYNTHROID, UNITHROID, others) is available in